Summary: It is well known that individuals differ in drug tolerance and propensity for addiction, and that both of these traits are highly heritable, resulting from interactions of many alleles. This multi-genic heritability makes diagnosing susceptibility and targeted treatment more difficult than for monogenic disorders. Despite the vast genetic heterogeneity, there are core principles of abuse and addiction that provide possibilities for new treatments: all drugs of abuse derive their hedonic qualities by upregulating dopamine signaling, and alterations in dopaminergic circuitry following repeated exposure are the root cause of addiction. It is therefore likely that many of the relevant genetic susceptibility loci are involved in the regulation of dopamine responses to drugs and triggering situations. If we refine our ability to precisely manipulate dopaminergic circuitry, we will be able to design treatments to counter the causes of abuse and addiction that are tailored to the individual, without necessarily needing to correct the causal alleles. The importance and potential of studying dopaminergic control systems to combat addiction have long been recognized; I propose a new and promising approach to rapidly identify the circuit and molecular principles of dopaminergic regulation. My lab has recently established two new systems for studying dopaminergic control of motivated behavior. In these systems, two separate populations of dopaminergic neurons provide dynamic motivational input into two distinct aspects of male mating behavior in Drosophila melanogaster: courtship and copulation. The small populations of dopaminergic neurons that control these behaviors are embedded within neural networks that precisely tune the amount of dopamine released so that the level of motivation matches the relevance of the behavioral goals. We study these behaviors because i) they show clear hallmarks of dopaminergic regulation of motivation; ii) they are robust, unambiguous, and easily quantified; iii) the underlying neurons are identifiable and genetically accessible through their expression of sexually dimorphic genes; and iv) the history of work in Drosophila suggests that the principles we uncover will apply to mammals. The main goal of this work is to generate new hypotheses and drug targets for interventions that will prevent the onset and persistence of drug addiction. The characterization of novel regulators of motivational dopaminergic circuitry will also be of use in identifying people at high-risk for abuse and addiction through their possession of altered alleles at these loci. This project is innovative because it combines circuit and molecular approaches in a simple model system to rapidly identify behaviorally-relevant regulators of dopaminergic activity. I do not believe that any such approach has been taken before and it therefore promises new discoveries and potential for treatments and diagnostics.